Mehmet Nur KAYA, Burcu CANER, Nilüfer AVCI

Onkolojide Yeni Bir Dönem: İmmunokonjugatlar

Klasik kemoterapötik ilaçlar hücre siklusunda arrest, hücre replikasyonunun durdurulması ve apopitoz indüksiyonu ile etki gösterir. Ancak bu ilaçların kanser hücresine spesifik olmaması nedeniyle belirli dozlar üzerinde kullanımı ölümcül toksisitelere neden olabilir. Bu nedenle ilacın etkinliği doz bağımlı olsa da, toksisite nedeniyle doz belirli bir seviyede sınırlanır. Yüksek yan etki nedeniyle sınırlanmış etkinlik, tedavide yeni moleküller geliştirilmesine neden olmuştur. Bu yeni geliştirilen ilaçlardan, immunokonjugatlar kanser hücresinin bir antijenine karşı geliştirilmiş antikor ve hücreye toksik olan bir ajanın (sitotoksik ilaç, radyoizotop, toksin) güçlü bir bağ ile birleştirilmesiyle oluşturulur. Bu bağ, antikor ve ajanın hücreye ulaşmadan ayrılmamasını ve ajanın hücre içine ulaşmasını sağlar. Bu mekanizma, immunokonjugatların kanser hücresine spesifik olmasını sağlar. Bu makalede, geleceğin popüler tedavisi olabilecek immunokonjugatların özelliklerini ve neden daha etkin olduklarını özetlemeyi amaçladık.

A New Terrm in Oncology: Immunoconjugates

Chemotherapy agents work classically via cell cycle arrest, inhibition of cell replication or induction of apoptosis. Unselectivity of these drugs at cell level limits their dose, where exceeding causes lethal toxicities, prevents dose increase even if it increases drug’s effect. This limited efficacy and high toxicity profile of chemotherapy drugs necessitate the search for new drugs. One of these new agents, immunoconjugates are molecules that combinean antibody against a specific antigen of cancer cell and a cytotoxic agent (cytotoxic drug, radioisotope, toxin) with a strong chemical bond. This bond ensures antibody and cytotoxic agent do not split before the drug reaches to the cancer cell, the cytotoxic agent is carried into the cell, that makes immunoconjugates cancer cell specific drugs. In this article, we aimed to summarize why immunoconjugates may be promising in cancer treatment, their structure and mechanism of action.

PDF

___

1. Anish Thomas, Beverly A Teicher. Antibody–drug conjugates for cancer therapy. Lancet Oncol 2016; 17: e254–62.
2. Yokota T, et al. Micro autoradiographic analysis of the normal organ distribution of radio iodin at single-chain Fv and other immunoglobulin forms. Cancer Res 1993; 53: 3776–83.
3. Ward ES, Zhou J, Ghetie V, et al. Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans. Int Immunol 2003; 15: 187–95.
4. Covell DG, et al. Pharmacokinetics of monoclonal immunoglobulin G1, F(ab') 2 and Fab' in mice. Cancer Res 1986; 46: 3969–78.
5. Adams GP, et al. Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Br J Cancer 1998; 77: 1405–12.
6. Wu AM. Engineered antibodies for molecular imaging of cancer. Methods. 2014; 65: 139–47.
7. Olafsen T, Sirk SJ, Olma S, et al. ImmunoPET using engineered antibody fragments: fluorine-18 labeled diabodies for same day imaging. Tumour Biol 2012; 33: 669–77.
8. Colcher D, et al. Pharmacokinetics and biodistribution of genetically-engineered antibodies. Q J Nucl Med 1998; 42: 225–41.
9. Daver N, Kantarjian H, Ravandi F, et al. A phase II study of decitabine and gemtuzumabozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome. Leukemia 2016; 30: 268–73.
10. Sanderson RJ. Invivo drug-linker stability of an anti-CD30 dipeptide-like dauristatin immunoconjugate. Clin Cancer Res 2005; 11: 843– 52.
11. Pasquetto MV, et al. Targeted drug delivery using immunoconjugates: Principles and applications. J Immunother 2011; 34: 611–28.
12. Koblinski JE, Ahran M, Sloane BF. Unraveling the role of proteases in cancer. Clin Chim Acta 2000; 291: 113–35.
13. Sjogren HO, et al. Human carcinomas in athymic mice and rat sands genetic at carcinomas in immunocompetant rates. Cancer Res 1997; 57: 4530–36.
14. Saleh MN, et al. Phase I trial of the antilewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors. J Clin Oncol 2000; 18: 2282–92.
15. Dosio F, Brusa P, Cattel L. Immunotoxins and anti cancer drug conjugate assemblies: the role of the link age between components. 2011; 3: 848– 83.
16. Sutherland MS, et al. Lysosomal trafficking and cysteine protease metabolism confer targetspecific cytotoxicity by peptide-linked anti-CD30- auristatin conjugates. J Biol Chem 2006; 281: 10540–47.
17. Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C study. J Clin Oncol 2007; 25: 4779–86.
18. US Department of Healthand Human Services. Ado-trastuzumab-emtansine. US Food and Drug Administration. 2013, www.fda.gov/Drugs/Information On Drugs/Approved Drugs/ucm 340913. htm.
19. Marx, JL. A Revolulation in Biotechnology. Marx, JL. editor. The Press Syndicate of the University of Cambridge; 1989. pp. 145-58.
20. Witzig TE, et al. Treatment with ibritumomab-tiuxetan radio immunotherapy in patients with rituximab-refractory follicular non- Hodgkin’s lymphoma. J Clin Oncol 2002; 20: 3262–69.
21. Kaminski MS, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cellnon- Hodgkin’s lymphomas. J Clin Oncol 2001; 19: 3918–28.
22. Timmerman L. Why good drugs sometimes fail: The Bexxar story. Xconomy. 2013 http://www.xconomy.com/national/2013/08/26/why -good-drugs-sometimes-fail-in-the-market-thebexxar- story/.
23. Reichert JM, et al. Monoclonal antibody successes in the clinic. Nat Biotechnol 2005; 23: 1073–78. 24. Song H, Sgouros G. Radio immunotherapy of solid tumors: searching for the right target. Current Drug Deliv 2011; 8: 26–44.